Abstract

BACKGROUND: Genome-wide association studies (GWAS) have not identified replicable genetic risk loci for stress or urgency urinary incontinence. METHODS: We carried out a discovery stage case control GWAS in three independent discovery cohorts of European women (n=8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in six additional studies of European ancestry (n=4,069). We collected bladder biopsies from women with incontinence to further investigate bladder expression of implicated genes and pathways (n=50) and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models in METAL, and whole transcriptome analyses using Affymetrix arrays, with replication with TaqMan PCR. RESULTS: In the discovery stage we identified 16 single nucleotide polymorphisms (SNPs) genotyped or imputed at five loci that reached genome-wide significance (p<5x10-8). In replication, rs138724718 on chromosome 2, near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the Endothelin 1 (EDN1) gene (replication p=0.0008) associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these two SNPs were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p<0.0001). CONCLUSION: We uncovered two new risk loci near the genes Endothelin 1 (EDN1), associated with urgency incontinence and Macrophage Receptor with Collagenous Structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense respectively.